This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Effective strategies for HIV prevention are urgently needed, but recent failures in key vaccine and 'microbicide'clinical trials highlight the need for new approaches validated in relevant animal models. In the continued absence of an effective vaccine, a microbicide that can be topically applied to the vagina may be the best hope for slowing vaginal HIV-1 transmission. However, such a microbicide must be highly effective and also inexpensive, so that it may be distributed to economically challenged areas where the epidemic is spreading most rapidly. We have previously shown that the CCR5 inhibitor PSC-RANTES can completely prevent vaginal transmission of R5 SHIV to macaques, but the cost of production limits its potential for a practical microbicide. We have thus developed two novel RANTES analogs that promise low cost recombinant production by fermentation. Here we show that these two new CCR5 inhibitors, 5P12-RANTES and 6P4-RANTES, protect fully against infection in the rhesus vaginal challenge model. These highly potent molecules, which are amenable to low-cost production, represent promising new additions to the microbicides pipeline.